Antibiotic bloat control composition and method of using same



United States Patent 3,234,086 ANT IBIOTIC-BLOAT CONTROL COMPOSITION AND METHOD OF USING SAME Paul A. Hartman and Norman L. Jacobson, Ames, Iowa,

and Richard H. Johnson, Palo Alto, Calif., assignors to Iowa State University Research Foundation, Inc., Ames, Iowa, a corporation of Iowa No Drawing. Filed May 12, 1961, Ser. No. 109,512

' 14 Claims. (Cl. 167-53) This invention relates to a bloat control preparation and method. The preparation and method of this invention have particular utility with domestic ruminants such as cattle and sheep.

The present application is a continuation-in-part of our copending application Serial No. 863,272, filed December 31, 1959, now abandoned.

Bloat is an affliction of livestock occurring in many parts of the world. The term usually refers .to' domestic ruminants; particularly the bovine'and ovine species. Ordinarily, bloat is characterized by an accumulation of gas and foam within the rumen or first compartment of the stomach in sufficient quantity that the normal pressure within the rumen is exceeded and distention of the rumen results. The distention of the rumen can be observed exteriorly as a swelling of the abdomen, particularly on the leftside. The extent of the distention increases with the severity of the condition. As seen in cattle, the first sign of'boat is generally a slight puffiness in the left paralumb'ar fossa. With increasing severity, the distention of the left paralumbar fossa becomes more marked, and eventually the right side of the animal becomes distended also. The skin becomes tight and drumlike to the touch (the term tympanites, often used to describe the syndrome, comes from a Greek phrase meaning drum-like"). The animal becomes restless and may become extremely nervous and excited if disturbed. As internal pressure increases still further, defecation and urination are frequent, incoordination is noted, the anus protrudes, and symptoms of respiratory distress appear. In the terminal stages, there is extreme abdominal distention, severe respiratory distress, cyanosis, prostration and death unless treated. One factor contributing to the seriousness of the condition is that the amount of time elapsing between the first and last states described above can be as little as ten to fifteen minutes.

Under normal conditions on the farm, the husbandman cannot afford a constant watch on a herd of grazing animals, particularly since bloat is often sporadic in nature, not occurring for a considerable time and then striking with no warning. Even when the herd is under con- 'stant surveillance, it may be difficult to drive animals that are bloated to a place where they can be restained and treated in time. Where adequate facilities for treatment are readily available, the tendency of otherwise docile animals to become extremely nervous and unmanageable maystill make treatment impossible. A further complication is the fact'that most of the less drastic treatments (from the standpoint'of undesirable side etfects on the animal) are relatively ineffective in severe cases. In

fact, the only relatively sure treatment involves an emergency rumenotomy, which at best requires a period of convalescenceand atworst can result in peritonitis and death from secondary causes. Damage resulting from bloat is not confined to death losses (although these are the usual data reported in statistical studies on the subject). Uncertainties involved often cause much inconvenienceand concern to the farmer. Furthermore, there are additional losses due to impaired production of meat and milk in animals afilicted with bloat. Another substantial loss occurs indirectly since farmers often refrain 3,Z34,0 Patented Feb. 8, 1!

from the use of legumes (which are high yielding nutritious) because of the risk of bloat.

Bloat as it occurs during the consumption of i legumes or the feeding of finely-ground grains is ch: terized by the development of a stable foam within rumen which, if unrelieved, can result in the serious t plications mentioned above. In large part, the inci in bloat in recent years has probably been due to cha in management and feeding practices and agreat incr in the acreage of legumes, alfalfa and ladino clover in ticular.

In the past, attempts have been made to prevent I through pasture management, grazing control, feedin dry roughage and the administration of anti-foai agents or antibiotics. None of these expedients proven practical.

Some attempts have been made to employ antibi for the prevention and treatment of bloat in rumin Heretofore, however, the experimental results with biotics for-bloat prevention have been relatively Ul cessful. While some antibiotics have been reports decreasing the incidence of bloat for a week or two, control has not been achieved over any extended p of time such as would be necessary under practical ditions of ruminant management where the animal eating a bloat-inducing diet. As a minimum, the biotic preparation should be capable of controlling in the animals receiving the preparation for three or weeks, and preferably for as long as two to three me From the standpoint of availability and cheapness,

- cillin would be a desirable antibiotic for use in COlltlt bloat, but, unfortunately, this antibiotic is efiectiv only relatively short periods of time, .usuallyless two weeks.

It is, therefore, a principal object of this inventii provide a novel bloat control preparation and me which will appreciably extend the efliective period of control, and which are adapted for practical comm application. Further objects and advantages will be cated in the following detailed specification.

This invention is based in part on the discovery the combination of penicillin with a macrolide anti is much more effective in preventing and controlling than penicillin alone. In other words, this inve; among other things, contemplates the use of an anti preparation containing both penicillin and a mac: antibiotic, and the administration. of such preparatit ruminants during periods in which they are eating inducing diets. Apparently, there is a synergistic between penicillin and macrolide antibiotics with n to bloat control. Such synergism is manifested be penicillin and various macrolide antibiotics such as e mycin, tylosin, and the like.

This invention is also based on the discovery th synergistic action of the antibiotic preparation i ther enhanced by employing both erythromycin ant sin in combination with penicillin. For reasons no understood, the combined administration of pen erythromycin, and tylosin gives a much more oil and longer period of control than when the same biotics are administered alternately or sequential];

For the purpose of the present invention, the'n proportions of the other synergistic antibiotics to p lin are of considerable importance. Preferably, f to 3 parts by weight of the macrolide antibiotic ployed per part of penicillin. For example,- when cillin, erythromycin, and tylosin are used in combii it is preferred to employ from 1 to 3 parts by of both erythromycin and tylosin per part of pen As a minimum, at least .5 part by weight of each 1 lide antibiotic should be used per part of penicilli the maximum is about 5 parts per part of penicillii ;such as erythromycin and/ortylosin; The prepons should'be administered in these amounts at rent intervals." For example, the preparations may .ven-daily or at least once every ftWO or, three days; results arezach-ievedwherethe antibiotic preparation mbined with afeed material which is administered in relatively 'uniform amounts over -theperiod in 1 'the'animals are'susee'ptible tOIblOZlt. procedures for oral administration can he used,

However,

as the incorporation. of the antibiotic preparation in t rinkingwaterfor the animals, 'salt or mineral mixfor the animals, etc. iere the .preparationsand method of this invention tsed with sheep, theamountof thezantibiotics ad-r .tered will usually be substantially less than'for cattle lse of the difierence in weight of, the. animals. For

ple, sheepmay be given from 2 to mg. of penicill admixturewith from 4 to40 mg. of each macro antibiotic." As in;the case of cattle,;it is preferred minister these amounts at frequent intervals, either oratleast every two or threedays It; is also rred to:combine: the antibiotic preparation with '-a material for the sheep, although'administration via ingwwater or minerals also can :be satisfactory.

though combinations of penicillin with a single olide antibiotic, such 33S, erythromycinor, tylosin, are ive, it is preferred to employ at least two maerolide iotics in the vcombination. Outstandin'g'results are vedwith preparations containingboth erythromycin' tylosin vin {00.l11bil13tl011 with penicillin If idesired,

antibiotics can also be includedi For example, the

:omycins, or tetracyclines are suitable, as in 'chloram-i col. From 1 to4 parts by weightof such additional,

iotics maybe employed per part of penicillin.

.ce the-amounts of the eombined antibiotic prepara-y to be administered. to each. animal Zare relatively 'it is desirable to incorporate the antibiotics in a naterial for the animal.

.y, to achieve a uniform distribution ;of theantibiotics ghout the feed material. The concentrationiof-the otics in the feed material mixture will, ofcourse,

id onu how much of the particular feed material is given to the animals perday. Usually, the amount e mixture to be ,given'will'fall within-the range- .1 lb. to ,2 lbs. per 'day for cattle, or .1 to 15 lb. 1y f'orrsheep. For example, in one preferred formuvfor-cattle, where the cattleare to be fed one I of the .feedmixture' per day, each pound of; the

re might contain 40 mg) of penicillin, .70 mg. of romycin, and 70 mg. of tylosin. It may be 'dee to pelletizezthe mixture to assurethat auniform )ution of the antibiotic will bemaintainedand to sture, such aslegume pasture, it will not ordinarily me. whenthe'a'nimals are being fed finely-ground or other bloat-inducing diets under. direct control e .cattle and sheep. raiser. Another 1 alternative is :lude' the antibioticsin thedrinlcingwater, salt,.or als supplied to the animals,

used herein the term cattle refers .to bovine aniincluding' calves, heifers, bulls, steerszand cowsof :eef cattle and .dairycattle breeds. By fruminants Various feed materials can; ed for this purpose, such as grains, milling by-prod-' Ie.g. wheat middlings), oil seed extraction by-prodetc. qDryblending procedures will usually be sa-tisis meant domestic":ruminants,=such as 'cattletandisheep The -term-penicillin is usedfiinits generic sense,; as: preferring to the. various: typesof penicillin, :such as penicillin' .G, penicillin tF, etc; ;1- The penicillin i. can t be nsed {I in itsisaltiform, such asthe solubletsodium :andpotassiumi;

salts, or the relatively insoluble tsalts like. procaine =peni-, cillin. The"term er.ylthromycint, intended to include all theclosely grelated forms 1015 this antibiotic :such as 2 erythromycin 7B and 502 Similarly,- the .term' strepto-w mycin" is used generically, as .rinclifding dihydrostreptoa mycin. Also, the term-Tetracycline? designates 'the closel y related group of'antibiotics: which includes chlortetras cycline, oxytetracycline; etcut The term' rn acrolidel is usedsgenerically'p but ;iti.is not intended.to includetfithezv I poly'ene :macrocyclicilactones or. the polypeptideilactones.

This invention: is further :illustrated by the. following 'EXAMPLEU The following formulations'are illustrativeofantibio'ticcontaining-feed mixtures which may be used in practicing the present tinventionr Formulation A Mgjlbbfeedw Penicillin 40.} Erythromycin i i l 701.

' Formulation'B I Penicillin 40.'

Tylosin- FormulatiomC Penicillin 80, Erythromycin i v .140? Tylosin .1401

F ormula'tiom D I Penicillin 400 Erythromycin. "7.... 700... Tylosin 700." Chloramphenicol ,1000 i Oxytetracycline ,1000.

It will be understood that the. above formulations would}; the combined with suitable ;fee'd.materia1ssuch as :wheat 21 middlin gs, linseed meal, wheathran, ,etct; For. thebovin'e 5' group (cg. diary cattle and: beef cattle), where t the? animals range inyweight: from 400 to '1000-lbs., Formu: lations A- and B should :be ;used at the-rate of '1 1b., penxa animal per day, FormulatiomC 'atathe rate of /2 ;lb. per. animal per day, and Formulation Dfat vthe eratetof' :1 1b. pernanimal ;.per; day. For :largerw or ssmalled cattle,: the, amountcan be varied. in proportion to weight. ,For sheep approximately one-fourth :to one-fifth the amount}. for; cattle: would beflused.

EXAMPLE-2 A preparation for con-trolling bloat' in rcattlel- :is; =pre pared .bymixing gr=amstofpenicillin,- g. of erythromycin 1140 g. of tylo'sin, and 140. g. ofistreptomycimwith av ton (20001 lbs.) of wheatt middlingsjcontaining 5% molasses; To" assure uniform distribution,- the; antibiotic; i

ingredients are first mixed zwith ia small amount (1010 s 20 lbs.) 'of the middlings and thereafter.:thisipre-mix:is combined with therest of thetmaterialql 'lhesestepszeant. be carried out by a 'dry mixing operatiomx lftdesired other edible tveget-able materials can he substituted'fsuch i as cornyoats; lin'seed -mealywheat, bran,zetc. Theme-.- sulting feed material isfthenvsuitableforeadi'ninistration animal; per :day.

to cattleiat the-rate.of;*approximatel eionea.:pound-,:per

EXAMPLE 3 one-half pound of t the grain'mixture was: fed dially perhead to a group of 11 animals (average weight, approximately 660 pounds). An equal quantity of grain alone was given to a control group of animals. The animals grazed relatively pure second-year alfalfa twice daily, from 7:00 to 10:00 a.m. and from 4:00 to 7:00 pm. Bloat severity was observed continuously from horseback during each grazing period and for one hour afterwards, making a total of 4 hours. The evaluation was visual, using the Johnson scale as described in J. Animal Science, Vol. 17, pp. 893-902 (1958). This scale is summarized below in Table A;

TABLE A.DESCRIPTION OF SCALE USED IN ASSIGN- ING ,BLOAT SCORES Score: Description 0- No bloat-no distention in left par-alumbar fossa.

1.... Slight--slight distention in left paralumbar fossa;

Over a 23 day period, 22 bloat scores of No. 3 or higher (moderate to terminal) were observed in the control group, while only 2 were observed in the treated group. A'total of 19 observations of mild bloat (score No. 2) were also made for the control group as compared to only one such observation for the treated group.

In another test where erythromycin was fed at the same level, where the penicillin level was 23.3 mg. per pound of grain, and where spontin and novobiocin also were included, the results over a 26 day period were: control group, cases of No. 3 or higher and 52 cases of No. 2; antibiotic group, one case of No. 3 and one of No. 2.

- EXAMPLE 4 Penicillin, erythromycin, and tylosin were added to drinking water at appropriate levels so that each animal received a daily dose of 40, 70 and 70 mg., respectively. Treatment was continued daily for approximately 50 days. A group of 15 cattle (average weight, 592 pounds) received this treatment, while another group of 15 animals (average weight 639 pounds) was retained as controls. Grazing practices and evalution of the degree of bloat were similar to those indicated in Example 3.

Results of the trials are summarized in Table B. The combination was effective for the full period of treatment. A shown in Table B, considerable bloat was observed inthe control animals.

TABLE B Mean No. Cases Group 1 No. of Max. of Bloat of Mean Dally Animals Bloat Score 3 or Wt. Gain Above Control 15 .254 41 .83

Treatedm, 1b .041 .4 1. 48

EXAMPLE 5 Penicillin, erythromycin, tylosin, chloromycetin, and oxytetracycline was admixed with grain at levels of 10.0, 17.5, 17.5, 25.0, and 25.0 mg. per pound of grain, respectively. Two pounds of the grain mixture were fed daily per head to a group of 15 cattle (average weight, 582 pounds). An equal quantity of grain alone was given to a control group of similar'size. The antibic levels were double about twelve days after initiation of treatment. The antibiotic combination was withdra approximately 92 days later, and the trials were termina 5 after another week. Grazing practices and evaluation the degree of bloat were similar to those given in l ample 3.

Results are summarized in Table C. The lower lei of antibiotics were adequate for the early period. '1 10 higher antibiotic levels gave excellent control until treatment was withdrawn. Much bloat'w-as observed lowing withdrawal of the antibiotic treatment. As she in Table C, considerable bloat was observed in the c -trol animals.

A preparation for controlling bloat in ruminants 1 be prepared by mixing the following: 10 lb. CaC0 lb. CaHPO 10 lb. NaCl, 5 grams penicillin, 9 gr erythromycin, and 9 grams tylosin. T his mineral mix is suitable for feeding to cattle or sheep.

While in the foregoing specification this invention been described in relation to certain specific embodim thereof and many details have beenset forth for the r pose of illustration, it will Ibe apparent to those sk in the art that the invention is susceptible to other bodiments and that many of the detailsdescribed he can be varied considerably without departing from basic principles of the invent-ion.

We claim:

40 1. A preparation for controlling bloat in rumin comprising penicillin, erythromycin, and tylosin in mixture with a ruminant feed material, said preparz containing from .5 to 5 parts by weight each of e: romycin and tylosin per part of penicillin.

2. A preparation for controlling bloat in rumin comprising penicillin, erythromycin, and tylosin in mixture with a ruminant feed material, said prepar: containing from 1 to 3 parts by weight each of e romycin and tylosin per part of penicillin, said pro tion also containing at least one other antibiotic 8811 from the group consisting of streptomycin, tetracyi and chroamphenicol; and other antibiotics being ployed in amounts of from 1' to 4 parts by weigh part of penicillin.

3'. A preparation for controlling bloat in rumir comprising penicillin together with erythromycin tylosin, said preparation containing from .5 to -5 [by weight each of erythromycin and tylosin per pa penicillin.

4. A preparation for controlling bloat in rumir comprising penicillin together with erythromycin tylosin, said preparation containing from 1 to 3 par weight each of erythromycin and tylosin per pa penicillin.

5. A preparation for controlling bloat in rumi1 comprising a mixture of at least three antibiotics formly dispersed in a carrier administerable to rumii said antibiotics including in combination peni erythromycin, and tylosin, said preparation cont:

from .5 to 5 parts by weight each of said erythror and tylosin per part of penicillin.

" 6. The preparation of claim 5 in which said prt tion also contains at least one other antibiotic se from the group consisting of streptomycin tetracy and ehloramphenicol, said antibiotics being employ nts of from 1 "to 4 parts by weight per part :of illin. The method of controlling bloat in cattle-for an dedperiod oftime while said cattle are continuing aibloat-inducing diet, comprising orally administersaid cattle a preparation containing penicillin, erythcin, and tylosin, from 5 to 5 parts bywcight each id erythromycin andtylosin being present per part nicillinfsaid preparation being: administeredat the 3f to 100 mg. of. penicillin peranimabper 24 A method for controlling bloat in cattle for an :led period of time while said cattle are continuing t a bloat-inducing diet,,comprising orally adminissv I. to said cattle a preparation containing penicillin,v

romycin, and tylosin uniformly dispersed .inza cardministerable to cattle,vfrom'l to 3 parts by weight of said erythromycin and said tylosin being present art of penicillin, said preparation being administered.

: rate of 10=to 100 mg. of penicillin per animal per urs.

The methodtof claim. 8 wherein said preparation :ontains at least one otherantibiotic selected-from roup consisting of 'strcptomycin tetracycline, and amphenicol, said other antibiotics being employed iounts of from 1 to 4 parts by weight per part of illin.

A method of controllingbloati in cattlefon an :ledperiod of time while said cattle are continuing aa bloat-inducing diet, comprising orally administer said cattle a preparation containing a plurality of i otics uniformly dispersed in a carrier administerablev ittle,- said antibiotics including penicillin; eryth- :in, tylosin, and at least one other antibiotic selected theq'group consisting of streptomycim:tetracycline :hloramphe'nicol, said preparation containing tfrom- 5 parts by weight each of erythromycin and tylosin;

art of pen-icillim saidother antibiotics beingemdlinamlountsof from 1 to 4 partsby weight per of penicillin, said administration being repeated a iity of times at spaced intervals and each administra- Jeing at the rate of 10 to 100 mgof penicillin per ll per 24 hours.;

The methodof controlling bloatiin sheep for an- :led period of time while said sheep are continuing a bloat-inducing diet, comprising orally administeb" 0 said sheep a preparation containing penicillin,

romycin, and tylosin, from .5 to 5 parts by weight of said erythromycin and tylosin'beingpresent per part of penicillin, saidl iprepar-ation i being administered at therate :of 2. to'20"mg.of; penicillin. penanimalcperf 24. hours.

7 '12.? A; methodtor controlling gbloat insheep. or an extended-periodof time whilesaidasheep are continuing}:

to eat a -bloat-inducinggdiet, comprising ;oral-ly admin-w istering to said sheep avpreparation containing penicillin;

erythromycin, and tylosin1uniforrnlyidispersedin a car rier administer-able to sheep,:from l to-3 partsiby wcighteach of: saidierythromycingandinsaid tylosirrbein'g present i peripart of penicillin, isaid{ preparation being-administered at=the rate=of=2 to 201mg; ofpenicillin per animalgpcrr 24? hours.

penicillin.v

14. A.'.methodi of controlling gbloat in sheep for an 5 7 extended ,periodof {time while said sheep are: continu:

ing tot-eat a;bloat inducingv diet, comprising orallyt;

administering to, :said: ishe'ep a pr eparation {containing a a plurality of antibiotics uniformly dispersed in a :carrier i bioticselected from-thegroup consistingof streptomycim;

'administerable to sheep, said anitbi'otics including penicil lin, erythromyc'in, tylosin," and at least oneaothe'r antitetracycline, ;and chloramphenicol; said ipreparation con tainin'g from 510 5 fparts-byvt'weight each of erythromyic and :tyloisin perwpart of penicillin; said othenantibiotics.

being employed in amounts of from -1 to 4 parts by weight perr part 1 of 1 penicillin; administration being: repeated; i. a plurality; oi times at; spaced intervals and; eachiia'dmina istration being ;at the :rate ;of 2am ZOQmgQgpi ipenicillin" per; animal per 24 hours."

References: Clted by the Examiner vBarrentine,;l Animal Science; Vol.- l 5,'?No. 2, May 1956;

pages 440-446. 5

- Powell; Antibioticsand:Chemotherapy, Vol. 3,1953, 7

pagesa IOI to 708;

Wallace, Antibiotics: andichemothenapy ,Vol: 3, Noi :3; 'Ma'rch1953,pages;271 and- -276'. V t

ULIAN s. :LEVITT, Primary Examiner; MORRIS o; womcz LEWIS. norrs; 'Examirieyrs;

Miller, *JournaloftDairy Science; Vol. '1962," pages UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,234,086 February a, 1966 Paul A. Hartman et a1.

It is hereby,' certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected .belou- Column 6, line 52, for "chroamphenicol; and" read chloramphenicol said column 8 line 29, for "erythromyic read erythromycin Signed and sealed this 17th day of January 1967.

Atlest:

ERNESTW. SWIDER EDWARD J. BRENNER Altesting Officer Commissioner of Patents 

1. A PREPARATION FOR CONTROLLING BLOAT IN RUMINANTS, COMPRISING PENICILLIN, ERYTHROMYCIN, AND TYLOSIN IN ADMIXTURE WITH A RUMINANT FEED MATERIAL, SAID PREPARATION CONTAINING FROM .5 TO 5 PARTS BY WEIGHT EACH OF ERYTHROMYCIN AND TYLOSIN PER PART OF PENICILLIN. 